Jonathan Yuen

Cancer incidence and mortality in women receiving estrogen and estrogen‐progestin replacement therapy—long‐term follow‐up of a Swedish cohort

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow‐up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen‐progestin combined brand was associated with an increasing relative risk of breast cancer with follow‐up time, the SIR reaching 1.4 (95% CI 1.1–1.8) after 10 years of follow‐up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6–5.9) in women prescribed estrogens alone, whereas those given an estrogen‐progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol‐progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow‐up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow‐up time. We conclude that hormone replacement increases the endometrial‐cancer risk after unopposed estrogens and the breast‐cancer risk—notably after estrogen‐progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.

Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study.

BACKGROUND/AIMS The risk of colorectal cancer increases in patients with ulcerative colitis, most markedly among young patients and/or those with extensive disease at onset. However, it is unknown whether individual risk can be predicted more precisely and whether cancer risk can be reduced by long-term treatment with sulfasalazine. METHODS In a population-based cohort of 3112 patients with ulcerative colitis, we compared 102 cases of colorectal cancer and 196 matched controls without cancer. Hospital records were used to abstract information on pharmacological therapy, disease activity, and extraintestinal manifestations. The relative risk (RR) of cancer was estimated by conditional logistic regression. RESULTS Pharmacological therapy, especially sulfasalazine, lasting at least 3 months was associated with a significant protective effect (RR, 0.38; 95% confidence interval [CI], 0.20-0.69) independent of disease activity. There was also a tendency to an independent protective effect for cigarette smoking (RR, 0.15; 95% CI, 0.02-1.25) and higher disease activity (RR, 0.80; 95% CI, 0.49-1.33). CONCLUSIONS The risk of colorectal cancer among patients with ulcerative colitis can be reduced through pharmacological therapy. This finding is consistent with the reports of a protective effect of aspirin among individuals in the general population.

Second primary cancers in patients with squamous cell carcinoma of the skin : A population-based study in Sweden

We studied second primary cancer among 25,947 patients diagnosed with squamous cell carcinoma of the skin (SCC) in Sweden between 1958 and 1992. In total, 5,706 patients developed a second primary cancer at any site, compared with an expected number of 2,651 [standardized incidence ratio (SIR) = 2.15; 95% confidence interval (CI) = 2.10–2.21]. Men below 60 years of age at diagnosis of SCC had higher SIR (2.5; CI = 2.2–2.8) with the highest risk during the first year of follow‐up (SIR = 9.2; CI = 6.9–12.2). If second primary SCC was excluded, the SIR was reduced to 1.30 (CI = 1.25–1.34); the relationships by sex, age and time since diagnosis remained similar. For skin cancer, the SIR for second SCC was markedly elevated (SIR = 15.6) and the risk of malignant melanoma was elevated 3‐fold. Significantly increased risks were found for most second cancers in squamous cell epithelium: lip (SIR = 5.2), respiratory organs (SIR = 1.7), esophagus (SIR = 1.5), cervix uteri (SIR = 2.2), and vulva including vagina (SIR = 2.3). There was a generally increased risk of almost 2‐fold for second cancer in hematopoietic or lymphoproliferative tissues. Slightly increased rates (SIR = 1.0–1.5) were seen for second tumors in digestive tissues. Finally, a high SIR (SIR = 5.5) was observed for second primary cancer in salivary glands. In conclusion, patients with SCC are at increased risk to develop new primary cancer, especially in skin, squamous cell epithelial and tobacco‐related tissues. Common risk factors among the tumor types might explain our findings, however, an intrinsic susceptibility among SCC patients to develop cancer is also possible. Int. J. Cancer 80:511–515, 1999.

Second cancers after medulloblastoma: population-based results from the United States and Sweden

Medulloblastoma, one of the most common central nervous system(CNS)tumors in children, requires aggressive multimodality therapy including surgery, radiation therapy, and occasionally chemotherapy. Given its intensive treatment regimen and improved survival during the past 20 years, it is likely that a cohort of survivors will result who may incur consequences of therapy, including a second cancer. We used population-based data from the United States and Sweden to estimate risks of second neo plasms in patients with histologically confirmed medulloblastoma (n = 1,262).Overall, there was a 5.4-fold excess of second neoplasms (95 percent confidence interval = 3.3-8.4) based on 20 observed and 3.7 expected cancers. The second cancers occurred eight to 432 months after initial diagnosis(median, 73 months) with significantly elevated ratios for all intervals examined except for less than one year after initial diagnosis. Significantly elevated risks were seen for cancers of the salivary glands, cervix uteri, brain and CNS, thyroid gland, and acute lymphoblastic leukemia. Of the 15second cancers with treatment data, seven occurred in the radiation field or within areas of scatter while two others may have been radiation-related. Although based on small numbers of second cancers, the results suggest that as survival increases, some patients with medulloblastoma will have an increased risk of a second cancer, particularly a radiation-related cancer. Thus, as survival improves, late-occurring consequences of diagnosis and treatment will need to be carefully assessed. Identification of patients hypersensitive to radiation therapy, such as those with Gorlin Syndrome, should also be attempted in order to reduce the sequelae from intensive radiation exposure.

Cholecystectomy and Colorectal Cancer

BACKGROUND An increased risk of large bowel cancer, especially of the right colon, following cholecystectomy has been reported in some studies but contradicted in others. The aim of this study was to settle this question by creating a cohort of cholecystectomy patients that was large enough and with a sufficient follow-up time to detect even weak associations. METHODS A population-based cohort consisting of 62,615 patients who underwent cholecystectomy was followed up for the occurrence of colorectal cancer up to 23 years. RESULTS There were 633 colorectal cancers versus 637.9 expected (standardized incidence ratio [SIR] = 0.99; 95% confidence interval [CI] = 0.92-1.07). Analyses of an extensive number of subgroups including sex, age at operation, duration of follow-up, underlying diagnosis, type of operation, and different cancer sites did not show any association. However, for cancer of the right colon among women, the risk was increased (SIR = 1.24; 95% CI = 1.03-1.48) most prominent 15 years or more after operation (SIR = 1.54; 95% CI = 1.03-2.22). CONCLUSIONS Overall, there is no excess risk of colorectal cancer following cholecystectomy, but consistent with some earlier reports, we observed an increased risk among women for right-sided colon cancer 15 years or more after operation.

Protective effect of fruits and vegetables on stomach cancer in a cohort of Swedish twins

Observational studies, primarily of a case‐control design, have shown an inverse association of fruit and vegetable consumption with the risk of stomach cancer, a finding tentatively attributed to anti‐oxidant vitamins. Ensuing randomized‐intervention trials of these vitamins, however, have been mostly negative. Therefore, the seemingly protective effect of fruit and vegetables in case‐control studies is suspected to be influenced by the information bias inherent in the retrospective assessment of exposure, particularly since pre‐conceptions about the wholesome effects of these foods are common among the public. Our aim was to examine the association of fruit and vegetable intake with the risk of stomach cancer in a prospective cohort study. Fruit and vegetable consumption was assessed in 1967 in 11,546 individuals in the Swedish Twin Registry, along with a wide range of potentially confounding factors. Complete follow‐up through 1992 was attained through record linkage to the National Cancer and Death Registers. The relative risk of stomach cancer was estimated in proportional hazards models, with confidence intervals (CIs) adjusted for correlated outcomes. The risk of stomach cancer was inversely related to fruit and vegetable consumption. Controlling for potentially confounding factors, the relative risk among subjects with the lowest compared to those with the highest intake was 5.5 (95% CI 1.7–18.3) with a statistically significant dose–risk trend (p < 0.05). Our results indicate that information bias is not likely to explain the discrepancy between the results of observational studies and of randomized‐intervention trials. Int. J. Cancer 76:35–37, 1998.© 1998 Wiley‐Liss, Inc.

Risk of extrahepatic bileduct cancer after cholecystectomy

The aetiology of cancer of the extrahepatic bile duct is unknown. Gallstones have been proposed to be a risk factor on the basis of ecological and epidemiological evidence. As gallstones are formed in the gallbladder, the occurrence of extrahepatic bileduct cancer in patients after cholecystectomy is of interest. All patients (62,734) who had had a cholecystectomy during 1965-1983 within the Uppsala Health Care Region, Sweden, were followed up to the end of 1987. Excluding the first year of follow-up, 23 cancers of the extrahepatic bileduct occurred vs 26.3 expected for a standardised incidence ratio (SIR) of 0.88 (95% confidence interval [CI] 0.56-1.31). 10 years or more after operation there was a greater reduction of risk (SIR = 0.27; 95% CI 0.06-0.80). Similar patterns were observed for men and women, and among patients who had undergone cholecystectomy only compared with those who had had their common bileducts explored. To assess surveillance bias the incidence of primary liver cancer was also analysed: SIR = 1.15; 95% CI 0.91-1.44 overall, and 10 years or more after cholecystectomy SIR = 0.98; 95% CI 0.66-1.40. This study shows a reduced risk of extrahepatic bileduct cancer 10 or more years after cholecystectomy, indicating that gallstones may be a cause of this cancer.

Hormone replacement therapy and major risk factors for reproductive cancers, osteoporosis, and cardiovascular diseases: evidence of confounding by exposure characteristics.

Observational studies have yielded reports on long-term effects of hormone replacement therapy (HRT) for cardiovascular, osteoporosis-related, and cancer diseases. There is concern that risk estimates may be confounded by complex mechanisms of selection with regard to important risk determinants. In this study, we tested the hypothesis that baseline characteristics of women vary with exposure characteristics, i.e., the choices of complying with prescriptions, using different compounds and regimens, and continuing intake long-term. We analyzed the prevalence of relevant risk factors and their relationships to characteristics of exposure among 11,211 Swedish women who had received prescription for HRT. Associations were studied through logistic regression, with comparisons of women with ever-use versus non-compliance, long-term (73+ months) versus short-term use (1-72 months), intake of conjugated estrogens versus estradiol compounds, and intake of estrogens only versus estrogens combined with progestins, respectively. We found that women denying intake of using HRT short-term had higher parity, earlier age at first birth and a lower prevalence of hysterectomy or oophorectomy than those complying or exposed long-term. A high level of education was associated with compliance and long-term exposure, and heavy physical exercise and high intake of food fibers were associated with compliance. Climacteric symptoms were associated with compliance, long-term intake and use of conjugated estrogens, whereas a history of oral contraceptive intake was associated with use of estrogens alone without progestins. We conclude that selection biases in studies of HRT effects are important and complex in that they may vary with the reported exposure. Our findings are important, as they point to the need for improved methods for measuring, in particular, factors linked to lifestyle and health behavior, in order to account more fully for confounding in the analyses of risk relationships.

Cancer risk in patients with earlier diagnosis of cutaneous melanoma In situ

We calculated the short‐term and long‐term risks of developing cancer among 3,766 patients with a diagnosis of cutaneous melanoma in situ in Sweden from 1958 to 1992. In total, 393 patients developed a primary cancer at any site compared with an expected number of 177 [standardized incidence ratio (SIR) = 2.2, 95% confidence interval (CI) = 2.0–2.4]. Patients below 60 years of age at diagnosis had the highest SIR (2.7, 95% CI = 2.3–3.2). The overall risks were similar between men and women. The highest risk was seen during the first year of follow‐up, though the risk remained elevated also after 15 or more years of follow‐up. For specific sites, the highest SIR was found for developing invasive cutaneous malignant melanoma (SIR = 22.2). The risk of subsequent primary non‐melanoma skin cancer was elevated 8‐fold in men and almost 7‐fold in women. An elevated risk was also found for female breast cancer (SIR = 1.4). Especially among women, other sites with increased cancer risk (though not significant) were non‐Hodgkins lymphoma (SIR = 1.9), multiple myeloma (3.2) and cancers of the colon (1.6) and pancreas (1.6). In conclusion, patients with melanoma in situ run a generally increased risk of developing primary cancers, especially cutaneous malignant melanoma and non‐melanoma skin cancer. The increased long‐term risk of cancer after diagnosis of melanoma in situ may be due to continuing carcinogenic exposure or to intrinsic tumor susceptibility. Int. J. Cancer 83:314–317, 1999.